Non-alcoholic Fatty Liver Disease
Conditions
Brief summary
The primary objective of this study is the proof of mechanism and support of dose finding, together with the safety evaluation in patients with clinical evidence of NASH. To gain further insight into clinical effects of AOC3 inhibition on NASH further exploratory analyses of biomarkers related to NASH and liver fibrosis will be performed. This will include the effect of BI 1467335 on reduction of secondary biomarker endpoints (ALT, AST, AP, γ-GT and CK18 fragments). Safety will be assessed throughout the study to provide key information regarding the use of BI 1467335 in patients with NASH.
Interventions
DRUGBI 1467335
once daily
DRUGPlacebo
once daily
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Clinical evidence of NASH defined as a. histological evidence of NASH (no more than 3 years prior to screening) OR b. clinical imaging results suggestive of NASH (no more than 3 years prior to screening) OR within the screening phase, imaging procedures performed as per local standard) i. evidence of hepatic steatosis \>5% measured by the MRI-PDFF) or assessed as moderate to severe steatosis (raised echogenicity of the liver parenchyma) by ultrasound AND ii. evidence of liver fibrosis defined as mean stiffness \> 3.64 kPa as measured by the MRE protocol or mean stiffness \> 7.2 kPa as measured by ultrasound based transient elastography (Fibroscan®) * Increased ALT defined as a. ALT \>1.5 ULN at screening and ALT \>1.25 ULN in a local lab within 1 week to 3 months prior screening OR b. Historic ALT \> 1.25 ULN more than 3 months prior to screening and two consecutive ALT \> 1.5xULN must be confirmed at least 1 week apart within the screening period * Age ≥ 18 and ≤75 years at screening * BMI ≥25kg/m2 and \<45kg/m2 at screening * Stable body weight defined as less than 5% change in body weight in the 3 months prior to screening while being treated with the standard of care and not treated with anti-obesity medication at screening. * Treatment with Antidiabetic concomitant medication including any insulin regimen needs to be stable for 3 months, and treatment with vitamin E needs to be stable for 6 months prior to informed consent and expected to be stable throughout the trial. All other concomitant medication has to be stable for at least 4 weeks prior screening. Concomitant medications taken to treat acute conditions (e.g. headache, sinusitis) for a short period (\< 7 days) are permissible, if not otherwise prohibited. * For female patients: Women of childbearing potential\* can be randomized after a negative pregnancy test and under adequate contraception with two methods, of which at least one is highly effective, during the trial.\* A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. Tubal ligation is NOT a method of permanent sterilisation. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. * Signed and dated written informed consent in accordance with GCP and local legislation prior to admission to the trial.
Exclusion criteria
* Current or history of significant alcohol consumption (defined as intake of \>210g/week in males and \>140g/week in females on average over a consecutive period of more than 3 months) or inability to reliably quantify alcohol consumption based on investigator judgement. * Prior participation in an interventional NASH trial 6 months before baseline or 5 times halflife of the investigational drug, whichever is longer. * Prior or planned bariatric surgery during study conduct, except gastric-band surgery more than 2 years prior to screening (including adjustments) with a stable body weight within the last 12 months. * Use of drugs historically associated with liver injury, hepatic steatosis or steatohepatitis in the 4 weeks prior to screening. * History of liver cirrhosis (fibrosis stage 4), or hepatic decompensation (e.g. ascites, hepatic encephalopathy, variceal bleeding, etc.) or history of other forms of chronic liver disease (for example Hepatitis B, Hepatitis C, autoimmune liver disease, primary biliary sclerosis, primary sclerosing cholangitis, Wilsons disease, hemochromatosis, A1At deficiency, history of liver transplantation). * Active known chronic or relevant acute infections, such as HIV (Human Immunodeficiency Virus), \\viral hepatitis, or tuberculosis. QuantiFERON® TB test and HBs Ag test will be performed during screening. Patients with a positive test result may participate in the study if further work up (according to local practice/guidelines) establishes conclusively that the patient has no evidence of active infection. * Solid liver lesions other than haemangiomas. \-- Suspicion or diagnosis or history of hepatocellular carcinoma (HCC) * eGFR \<60ml/min/1.73m2 at screening (CKD-EPI formula). * ALT \>5.0 ULN at screening. * Platelet count \< 150.000/μL * Bilirubin level \> ULN (except for known Gilbert´s disease with a conjugated bilirubin of \< 0.3 mg/dL)) * Uncontrolled diabetes defined as an HbA1c ≥9.5% in the 3 months prior to or at screening. * Diagnosis of a serious or unstable disease including hepatic (other than NASH), renal, gastroenterologic, respiratory, cardiovascular (including ischemic heart disease), endocrinologic, neurologic , psychiatric, immunologic, or hematologic disease and other conditions that, in the clinical judgment of the investigator, are likely to interfere with the analyses of safety and efficacy in this study. Patients with an expected life expectancy of less than 2 years are also excluded. * Major surgery (major according to the investigator's assessment) performed within 12 weeks prior to randomisation or planned during study conduct, e.g. hip replacement. * Any documented active or suspected malignancy or history of malignancy within 5 years prior to screening, except appropriately treated basal cell carcinoma of the skin or in situ carcinoma of uterine cervix. * Patients who must or wish to continue the intake of restricted medications or any drug considered likely to interfere with the safe conduct of the trial. * Previous randomisation in this trial. * Currently enrolled in another investigational device or drug study, or less than 30 days since ending another investigational device or drug study(s), or receiving other investigational treatment(s). * Chronic drug abuse or any condition that, in the investigator's opinion, makes them an unreliable study subject or unlikely to complete the trial. * Women who are pregnant, nursing, or who plan to become pregnant while in the trial. * Patients with Wolff-Parkinson-White Syndrome, baseline QTc \> 450 ms, family history of long QT, or on medication prolonging QT time at screening or planned initiation during the trial. * Any other clinical condition that, in the opinion of the investigator, would jeopardize patient safety while participating in this clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Plasma Amine Oxidase Copper-containing 3 (AOC3) Activity After 12 Weeks of Treatment, Relative to Baseline in Percent | Day 1 (baseline), day 15, 29, 43, 57 and 85 (time t) 24 hours after the last dose of BI 1467335. | The patient-specific plasma AOC3 activity at time t (24 hours after the last dose in week 12) relative to baseline in percentage was calculated as follows: %AOC3at = \[(AOC3at - AOC3at,back) ⁄ (AOC3abase - AOC3abase,back)\]\*100 With AOC3at the AOC3 activity measured at time t, AOC3at,back the background noise at time t, AOC3abase the AOC3 activity measured at baseline and AOC3abase,back the background noise at baseline. A dose-response relationship was analysed using a non-linear regression model to estimate the daily dosage needed to reach 10% of AOC3 activity (i.e. 90% inhibition) 12 weeks after treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Alanine Aminotransaminase (ALT) After 12 Weeks of Treatment, Relative to Baseline in Percent | Day 1 (baseline), day 15, 29, 43, 57 and 85 (time t) 24 hours after the last dose of BI 1467335. | Alanine aminotransaminase (ALT) after 12 weeks of treatment, relative to baseline in percent. Number analyzed lower than N in PPS if there is missing data for specific timepoints. The unit of measure is: percentage relative to baseline = \[post baseline (time t)/baseline\]\*100% Statistical analyses description: A Mixed effects Model for Repeated Measurements (MMRM) over time including fixed effects for 'base', 'treatment', 'time', 'base\*time' interaction, and 'treatment\*time' interaction was performed. The MMRM estimates for the treatment effects at Week 12 and the corresponding covariance matrix were used to analyse the dose-response relationship using the Multiple contrast test (MCPMod). A test for non-flat dose-response relationship was first performed. If this relationship could be shown, the best fitting model out of a set of candidate models (Sigmoidal Emax, Logistic, Quadratic, Linear, Exponential, Linear logistic, Emax and Betamod) was to be selected and fitted. |
| Aspartate Aminotransferase (AST) After 12 Weeks of Treatment, Relative to Baseline in Percent | Day 1 (baseline), day 15, 29, 43, 57 and 85 (time t) 24 hours after the last dose of BI 1467335. | Aspartate aminotransferase (AST) after 12 weeks of treatment, relative to baseline in percent. Number analyzed lower than N in PPS if there is missing data for specific timepoints. The unit of measure is: percentage relative to baseline = \[post baseline (time t)/baseline\]\*100% Statistical analyses description: A Mixed effects Model for Repeated Measurements (MMRM) over time including fixed effects for 'base', 'treatment', 'time', 'base\*time' interaction, and 'treatment\*time' interaction was performed. The MMRM estimates for the treatment effects at Week 12 and the corresponding covariance matrix were used to analyse the dose-response relationship using the Multiple contrast test (MCPMod). A test for non-flat dose-response relationship was first performed. If this relationship could be shown, the best fitting model out of a set of candidate models (Sigmoidal Emax, Logistic, Quadratic, Linear, Exponential, Linear logistic, Emax and Betamod) was to be selected and fitted. |
| Alkaline Phosphatase (AP) After 12 Weeks of Treatment, Relative to Baseline in Percent | Day 1 (baseline), day 15, 29, 43, 57 and 85 (time t) 24 hours after the last dose of BI 1467335. | Alkaline phosphatase (AP) after 12 weeks of treatment, relative to baseline in percent. Number analyzed lower than N in PPS if there is missing data for specific timepoints. The unit of measure is: percentage relative to baseline = \[post baseline (time t)/baseline\]\*100% Statistical analyses description: A Mixed effects Model for Repeated Measurements (MMRM) over time including fixed effects for 'base', 'treatment', 'time', 'base\*time' interaction, and 'treatment\*time' interaction was performed. The MMRM estimates for the treatment effects at Week 12 and the corresponding covariance matrix were used to analyse the dose-response relationship using the Multiple contrast test (MCPMod). A test for non-flat dose-response relationship was first performed. If this relationship could be shown, the best fitting model out of a set of candidate models (Sigmoidal Emax, Logistic, Quadratic, Linear, Exponential, Linear logistic, Emax and Betamod) was to be selected and fitted. |
| Percentage of Participants With Drug-related Adverse Events (AEs) | Start of treatment till end of treatment + 28 days, up to 113 days. | Percentage of participants with drug-related adverse events (AEs). Percentages are calculated using total number of patients per treatment as the denominator. |
| Caspase-cleaved Cytokeratin 18 (CK-18 Caspase) After 12 Weeks of Treatment, Relative to Baseline in Percent | Day 1 (baseline), day 15, 29, 43, 57 and 85 (time t) 24 hours after the last dose of BI 1467335. | Caspase-cleaved cytokeratin 18 (CK-18 caspase) after 12 weeks of treatment, relative to baseline in percent. Number analyzed lower than N in PPS if there is missing data for specific timepoints. The unit of measure is: percentage relative to baseline = \[post baseline (time t)/baseline\]\*100% Statistical analyses description: A MMRM over time including fixed effects for 'base', 'treatment', 'time', 'base\*time' interaction, and 'treatment\*time' interaction was performed. The MMRM estimates for the treatment effects at Week 12 and the corresponding covariance matrix were used to analyse the dose-response relationship using the Multiple contrast test (MCPMod). A test for non-flat dose-response relationship was first performed. If this relationship could be shown, the best fitting model out of a set of candidate models (Sigmoidal Emax, Logistic, Quadratic, Linear, Exponential, Linear logistic, Emax and Betamod) was to be selected and fitted. |
| Total Cytokeratin 18 (CK-18 Total) After 12 Weeks of Treatment, Relative to Baseline in Percent | Day 1 (baseline), day 15, 29, 43, 57 and 85 (time t) 24 hours after the last dose of BI 1467335. | Total cytokeratin 18 (CK-18 total) after 12 weeks of treatment, relative to baseline in percent. Number analyzed lower than N in PPS if there is missing data for specific timepoints. The unit of measure is: percentage relative to baseline = \[post baseline (time t)/baseline\]\*100%. Statistical analyses description: A Mixed effects Model for Repeated Measurements (MMRM) over time including fixed effects for 'base', 'treatment', 'time', 'base\*time' interaction, and 'treatment\*time' interaction was performed. The MMRM estimates for the treatment effects at Week 12 and the corresponding covariance matrix were used to analyse the dose-response relationship using the Multiple contrast test (MCPMod). A test for non-flat dose-response relationship was first performed. If this relationship could be shown, the best fitting model out of a set of candidate models (Sigmoidal Emax, Logistic, Quadratic, Linear, Exponential, Linear logistic, Emax and Betamod) was to be selected and fitted. |
| Gamma-glutamyltransferase (GGT) After 12 Weeks of Treatment, Relative to Baseline in Percent | Day 1 (baseline), day 15, 29, 43, 57 and 85 (time t) 24 hours after the last dose of BI 1467335. | Gamma-glutamyltransferase (GGT) after 12 weeks of treatment, relative to baseline in percent. Number analyzed lower than N in PPS if there is missing data for specific timepoints. The unit of measure is: percentage relative to baseline = \[post baseline (time t)/baseline\]\*100% Statistical analyses description: A Mixed effects Model for Repeated Measurements (MMRM) over time including fixed effects for 'base', 'treatment', 'time', 'base\*time' interaction, and 'treatment\*time' interaction was performed. The MMRM estimates for the treatment effects at Week 12 and the corresponding covariance matrix were used to analyse the dose-response relationship using the Multiple contrast test (MCPMod). A test for non-flat dose-response relationship was first performed. If this relationship could be shown, the best fitting model out of a set of candidate models (Sigmoidal Emax, Logistic, Quadratic, Linear, Exponential, Linear logistic, Emax and Betamod) was to be selected and fitted. |
Countries
Belgium, Canada, France, Germany, Ireland, Netherlands, Spain, United Kingdom, United States
Participant flow
Recruitment details
This study is a multi-centre, double-blind, parallel-group, randomised, placebo-controlled phase IIa study to investigate safety, tolerability, pharmacodynamics, and pharmacokinetics of different doses of orally administered BI 1467335 (for 12-weeks) compared to placebo in patients with clinical evidence of Non-alcoholic steato-hepatitis (NASH).
Pre-assignment details
All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria. Subjects were not to be allocated to a treatment group if any of the entry criteria were violated.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Matching placebo taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated placebo tablets were supplied. For blinding reasons, all patients took 5 tablets placebo daily. | 32 |
| BI 1467335 1 Milligram (mg) 1 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strengths. For blinding reasons, all patients took 5 tablets verum or placebo daily. | 16 |
| BI 1467335 3 Milligram (mg) 3 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strengths. For blinding reasons, all patients took 5 tablets verum or placebo daily. | 16 |
| BI 1467335 6 Milligram (mg) 6 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strengths. For blinding reasons, all patients took 5 tablets verum or placebo daily. | 17 |
| BI 1467335 10 Milligram (mg) 10 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strengths. For blinding reasons, all patients took 5 tablets verum or placebo daily. | 32 |
| Total | 113 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | follow-up not completed as planned | 0 | 1 | 1 | 0 | 1 |
| Overall Study | Lost to Follow-up | 0 | 2 | 1 | 0 | 1 |
| Overall Study | Not Treated | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 | 1 | 2 |
Baseline characteristics
| Characteristic | Placebo | BI 1467335 1 Milligram (mg) | BI 1467335 3 Milligram (mg) | BI 1467335 6 Milligram (mg) | BI 1467335 10 Milligram (mg) | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 51.8 years STANDARD_DEVIATION 12.3 | 52.6 years STANDARD_DEVIATION 13.3 | 53.9 years STANDARD_DEVIATION 11.5 | 48.2 years STANDARD_DEVIATION 10.1 | 49.8 years STANDARD_DEVIATION 14 | 51.1 years STANDARD_DEVIATION 12.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 11 Participants | 5 Participants | 5 Participants | 4 Participants | 8 Participants | 33 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 21 Participants | 11 Participants | 11 Participants | 13 Participants | 24 Participants | 80 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Plasma amine oxidase copper-containing 3 (AOC3) baseline concentration | 471.4063 microgram per liter (µg/l) STANDARD_DEVIATION 165.6802 | 537.7143 microgram per liter (µg/l) STANDARD_DEVIATION 204.41 | 498.0000 microgram per liter (µg/l) STANDARD_DEVIATION 141.0225 | 527.2941 microgram per liter (µg/l) STANDARD_DEVIATION 142.3722 | 516.1613 microgram per liter (µg/l) STANDARD_DEVIATION 144.0727 | 504.9636 microgram per liter (µg/l) STANDARD_DEVIATION 157.4936 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 30 Participants | 14 Participants | 16 Participants | 17 Participants | 32 Participants | 109 Participants |
| Sex: Female, Male Female | 13 Participants | 10 Participants | 8 Participants | 9 Participants | 18 Participants | 58 Participants |
| Sex: Female, Male Male | 19 Participants | 6 Participants | 8 Participants | 8 Participants | 14 Participants | 55 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 32 | 0 / 16 | 0 / 16 | 0 / 17 | 0 / 32 | 0 / 81 |
| other Total, other adverse events | 18 / 32 | 12 / 16 | 12 / 16 | 13 / 17 | 17 / 32 | 54 / 81 |
| serious Total, serious adverse events | 1 / 32 | 1 / 16 | 1 / 16 | 0 / 17 | 0 / 32 | 2 / 81 |
Outcome results
Primary
Plasma Amine Oxidase Copper-containing 3 (AOC3) Activity After 12 Weeks of Treatment, Relative to Baseline in Percent
The patient-specific plasma AOC3 activity at time t (24 hours after the last dose in week 12) relative to baseline in percentage was calculated as follows: %AOC3at = \[(AOC3at - AOC3at,back) ⁄ (AOC3abase - AOC3abase,back)\]\*100 With AOC3at the AOC3 activity measured at time t, AOC3at,back the background noise at time t, AOC3abase the AOC3 activity measured at baseline and AOC3abase,back the background noise at baseline. A dose-response relationship was analysed using a non-linear regression model to estimate the daily dosage needed to reach 10% of AOC3 activity (i.e. 90% inhibition) 12 weeks after treatment.
Time frame: Day 1 (baseline), day 15, 29, 43, 57 and 85 (time t) 24 hours after the last dose of BI 1467335.
Population: Per Protocol Set (PPS): Patients who signed informed consent, were treated with at least one dose of the trial medication, without any important protocol deviations leading to exclusion and who had non-missing baseline and at least one non-missing post-baseline and on-treatment measurement on any primary, secondary or further biomarker endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Plasma Amine Oxidase Copper-containing 3 (AOC3) Activity After 12 Weeks of Treatment, Relative to Baseline in Percent | 102 Percentage relative to baseline | Standard Deviation 13 |
| BI 1467335 1 Milligram (mg) | Plasma Amine Oxidase Copper-containing 3 (AOC3) Activity After 12 Weeks of Treatment, Relative to Baseline in Percent | 24.0 Percentage relative to baseline | Standard Deviation 11.9 |
| BI 1467335 3 Milligram (mg) | Plasma Amine Oxidase Copper-containing 3 (AOC3) Activity After 12 Weeks of Treatment, Relative to Baseline in Percent | 13.1 Percentage relative to baseline | Standard Deviation 10.4 |
| BI 1467335 6 Milligram (mg) | Plasma Amine Oxidase Copper-containing 3 (AOC3) Activity After 12 Weeks of Treatment, Relative to Baseline in Percent | 8.27 Percentage relative to baseline | Standard Deviation 5.19 |
| BI 1467335 10 Milligram (mg) | Plasma Amine Oxidase Copper-containing 3 (AOC3) Activity After 12 Weeks of Treatment, Relative to Baseline in Percent | 2.06 Percentage relative to baseline | Standard Deviation 3.62 |
Comparison: D10: Estimated dose reaching \<=10% activity the first time.non-linear regression
Secondary
Alanine Aminotransaminase (ALT) After 12 Weeks of Treatment, Relative to Baseline in Percent
Alanine aminotransaminase (ALT) after 12 weeks of treatment, relative to baseline in percent. Number analyzed lower than N in PPS if there is missing data for specific timepoints. The unit of measure is: percentage relative to baseline = \[post baseline (time t)/baseline\]\*100% Statistical analyses description: A Mixed effects Model for Repeated Measurements (MMRM) over time including fixed effects for 'base', 'treatment', 'time', 'base\*time' interaction, and 'treatment\*time' interaction was performed. The MMRM estimates for the treatment effects at Week 12 and the corresponding covariance matrix were used to analyse the dose-response relationship using the Multiple contrast test (MCPMod). A test for non-flat dose-response relationship was first performed. If this relationship could be shown, the best fitting model out of a set of candidate models (Sigmoidal Emax, Logistic, Quadratic, Linear, Exponential, Linear logistic, Emax and Betamod) was to be selected and fitted.
Time frame: Day 1 (baseline), day 15, 29, 43, 57 and 85 (time t) 24 hours after the last dose of BI 1467335.
Population: Per Protocol Set (PPS): Patients who signed informed consent, were treated with at least one dose of the trial medication, without any important protocol deviations leading to exclusion and who had non-missing baseline and at least one non-missing post-baseline and on-treatment measurement on any primary, secondary or further biomarker endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Alanine Aminotransaminase (ALT) After 12 Weeks of Treatment, Relative to Baseline in Percent | 92.66 Percentage relative to baseline | Standard Error 106.55 |
| BI 1467335 1 Milligram (mg) | Alanine Aminotransaminase (ALT) After 12 Weeks of Treatment, Relative to Baseline in Percent | 97.32 Percentage relative to baseline | Standard Error 110.13 |
| BI 1467335 3 Milligram (mg) | Alanine Aminotransaminase (ALT) After 12 Weeks of Treatment, Relative to Baseline in Percent | 87.49 Percentage relative to baseline | Standard Error 109.79 |
| BI 1467335 6 Milligram (mg) | Alanine Aminotransaminase (ALT) After 12 Weeks of Treatment, Relative to Baseline in Percent | 80.61 Percentage relative to baseline | Standard Error 109.43 |
| BI 1467335 10 Milligram (mg) | Alanine Aminotransaminase (ALT) After 12 Weeks of Treatment, Relative to Baseline in Percent | 77.57 Percentage relative to baseline | Standard Error 106.66 |
p-value: 0.0212MCPMod Sigmoidal Emax model fit.
Secondary
Alkaline Phosphatase (AP) After 12 Weeks of Treatment, Relative to Baseline in Percent
Alkaline phosphatase (AP) after 12 weeks of treatment, relative to baseline in percent. Number analyzed lower than N in PPS if there is missing data for specific timepoints. The unit of measure is: percentage relative to baseline = \[post baseline (time t)/baseline\]\*100% Statistical analyses description: A Mixed effects Model for Repeated Measurements (MMRM) over time including fixed effects for 'base', 'treatment', 'time', 'base\*time' interaction, and 'treatment\*time' interaction was performed. The MMRM estimates for the treatment effects at Week 12 and the corresponding covariance matrix were used to analyse the dose-response relationship using the Multiple contrast test (MCPMod). A test for non-flat dose-response relationship was first performed. If this relationship could be shown, the best fitting model out of a set of candidate models (Sigmoidal Emax, Logistic, Quadratic, Linear, Exponential, Linear logistic, Emax and Betamod) was to be selected and fitted.
Time frame: Day 1 (baseline), day 15, 29, 43, 57 and 85 (time t) 24 hours after the last dose of BI 1467335.
Population: Per Protocol Set (PPS): Patients who signed informed consent, were treated with at least one dose of the trial medication, without any important protocol deviations leading to exclusion and who had non-missing baseline and at least one non-missing post-baseline and on-treatment measurement on any primary, secondary or further biomarker endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Alkaline Phosphatase (AP) After 12 Weeks of Treatment, Relative to Baseline in Percent | 96.62 Percentage relative to baseline | Standard Error 102.31 |
| BI 1467335 1 Milligram (mg) | Alkaline Phosphatase (AP) After 12 Weeks of Treatment, Relative to Baseline in Percent | 97.58 Percentage relative to baseline | Standard Error 103.56 |
| BI 1467335 3 Milligram (mg) | Alkaline Phosphatase (AP) After 12 Weeks of Treatment, Relative to Baseline in Percent | 100.52 Percentage relative to baseline | Standard Error 103.45 |
| BI 1467335 6 Milligram (mg) | Alkaline Phosphatase (AP) After 12 Weeks of Treatment, Relative to Baseline in Percent | 98.47 Percentage relative to baseline | Standard Error 103.34 |
| BI 1467335 10 Milligram (mg) | Alkaline Phosphatase (AP) After 12 Weeks of Treatment, Relative to Baseline in Percent | 94.71 Percentage relative to baseline | Standard Error 102.34 |
p-value: 0.3324MCPMod exponential model fit.
Secondary
Aspartate Aminotransferase (AST) After 12 Weeks of Treatment, Relative to Baseline in Percent
Aspartate aminotransferase (AST) after 12 weeks of treatment, relative to baseline in percent. Number analyzed lower than N in PPS if there is missing data for specific timepoints. The unit of measure is: percentage relative to baseline = \[post baseline (time t)/baseline\]\*100% Statistical analyses description: A Mixed effects Model for Repeated Measurements (MMRM) over time including fixed effects for 'base', 'treatment', 'time', 'base\*time' interaction, and 'treatment\*time' interaction was performed. The MMRM estimates for the treatment effects at Week 12 and the corresponding covariance matrix were used to analyse the dose-response relationship using the Multiple contrast test (MCPMod). A test for non-flat dose-response relationship was first performed. If this relationship could be shown, the best fitting model out of a set of candidate models (Sigmoidal Emax, Logistic, Quadratic, Linear, Exponential, Linear logistic, Emax and Betamod) was to be selected and fitted.
Time frame: Day 1 (baseline), day 15, 29, 43, 57 and 85 (time t) 24 hours after the last dose of BI 1467335.
Population: Per Protocol Set (PPS): Patients who signed informed consent, were treated with at least one dose of the trial medication, without any important protocol deviations leading to exclusion and who had non-missing baseline and at least one non-missing post-baseline and on-treatment measurement on any primary, secondary or further biomarker endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Aspartate Aminotransferase (AST) After 12 Weeks of Treatment, Relative to Baseline in Percent | 93.77 Percentage relative to baseline | Standard Error 105.91 |
| BI 1467335 1 Milligram (mg) | Aspartate Aminotransferase (AST) After 12 Weeks of Treatment, Relative to Baseline in Percent | 105.17 Percentage relative to baseline | Standard Error 108.93 |
| BI 1467335 3 Milligram (mg) | Aspartate Aminotransferase (AST) After 12 Weeks of Treatment, Relative to Baseline in Percent | 90.09 Percentage relative to baseline | Standard Error 108.72 |
| BI 1467335 6 Milligram (mg) | Aspartate Aminotransferase (AST) After 12 Weeks of Treatment, Relative to Baseline in Percent | 84.12 Percentage relative to baseline | Standard Error 108.34 |
| BI 1467335 10 Milligram (mg) | Aspartate Aminotransferase (AST) After 12 Weeks of Treatment, Relative to Baseline in Percent | 87.83 Percentage relative to baseline | Standard Error 106.26 |
p-value: 0.127MCPMod Sigmoidal Emax model fit.
Secondary
Caspase-cleaved Cytokeratin 18 (CK-18 Caspase) After 12 Weeks of Treatment, Relative to Baseline in Percent
Caspase-cleaved cytokeratin 18 (CK-18 caspase) after 12 weeks of treatment, relative to baseline in percent. Number analyzed lower than N in PPS if there is missing data for specific timepoints. The unit of measure is: percentage relative to baseline = \[post baseline (time t)/baseline\]\*100% Statistical analyses description: A MMRM over time including fixed effects for 'base', 'treatment', 'time', 'base\*time' interaction, and 'treatment\*time' interaction was performed. The MMRM estimates for the treatment effects at Week 12 and the corresponding covariance matrix were used to analyse the dose-response relationship using the Multiple contrast test (MCPMod). A test for non-flat dose-response relationship was first performed. If this relationship could be shown, the best fitting model out of a set of candidate models (Sigmoidal Emax, Logistic, Quadratic, Linear, Exponential, Linear logistic, Emax and Betamod) was to be selected and fitted.
Time frame: Day 1 (baseline), day 15, 29, 43, 57 and 85 (time t) 24 hours after the last dose of BI 1467335.
Population: Per Protocol Set (PPS): Patients who signed informed consent, were treated with at least one dose of the trial medication, without any important protocol deviations leading to exclusion and who had non-missing baseline and at least one non-missing post-baseline and on-treatment measurement on any primary, secondary or further biomarker endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Caspase-cleaved Cytokeratin 18 (CK-18 Caspase) After 12 Weeks of Treatment, Relative to Baseline in Percent | 101.35 Percentage relative to baseline | Standard Error 111.15 |
| BI 1467335 1 Milligram (mg) | Caspase-cleaved Cytokeratin 18 (CK-18 Caspase) After 12 Weeks of Treatment, Relative to Baseline in Percent | 155.04 Percentage relative to baseline | Standard Error 117.61 |
| BI 1467335 3 Milligram (mg) | Caspase-cleaved Cytokeratin 18 (CK-18 Caspase) After 12 Weeks of Treatment, Relative to Baseline in Percent | 96.87 Percentage relative to baseline | Standard Error 117.54 |
| BI 1467335 6 Milligram (mg) | Caspase-cleaved Cytokeratin 18 (CK-18 Caspase) After 12 Weeks of Treatment, Relative to Baseline in Percent | 80.51 Percentage relative to baseline | Standard Error 116.32 |
| BI 1467335 10 Milligram (mg) | Caspase-cleaved Cytokeratin 18 (CK-18 Caspase) After 12 Weeks of Treatment, Relative to Baseline in Percent | 78.08 Percentage relative to baseline | Standard Error 111.59 |
p-value: 0.0042MCPMod Sigmoidal Emax model fit.
Secondary
Gamma-glutamyltransferase (GGT) After 12 Weeks of Treatment, Relative to Baseline in Percent
Gamma-glutamyltransferase (GGT) after 12 weeks of treatment, relative to baseline in percent. Number analyzed lower than N in PPS if there is missing data for specific timepoints. The unit of measure is: percentage relative to baseline = \[post baseline (time t)/baseline\]\*100% Statistical analyses description: A Mixed effects Model for Repeated Measurements (MMRM) over time including fixed effects for 'base', 'treatment', 'time', 'base\*time' interaction, and 'treatment\*time' interaction was performed. The MMRM estimates for the treatment effects at Week 12 and the corresponding covariance matrix were used to analyse the dose-response relationship using the Multiple contrast test (MCPMod). A test for non-flat dose-response relationship was first performed. If this relationship could be shown, the best fitting model out of a set of candidate models (Sigmoidal Emax, Logistic, Quadratic, Linear, Exponential, Linear logistic, Emax and Betamod) was to be selected and fitted.
Time frame: Day 1 (baseline), day 15, 29, 43, 57 and 85 (time t) 24 hours after the last dose of BI 1467335.
Population: Per Protocol Set (PPS): Patients who signed informed consent, were treated with at least one dose of the trial medication, without any important protocol deviations leading to exclusion and who had non-missing baseline and at least one non-missing post-baseline and on-treatment measurement on any primary, secondary or further biomarker endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Gamma-glutamyltransferase (GGT) After 12 Weeks of Treatment, Relative to Baseline in Percent | 91.37 Percentage relative to baseline | Standard Error 105.24 |
| BI 1467335 1 Milligram (mg) | Gamma-glutamyltransferase (GGT) After 12 Weeks of Treatment, Relative to Baseline in Percent | 99.42 Percentage relative to baseline | Standard Error 108.25 |
| BI 1467335 3 Milligram (mg) | Gamma-glutamyltransferase (GGT) After 12 Weeks of Treatment, Relative to Baseline in Percent | 92.44 Percentage relative to baseline | Standard Error 108.09 |
| BI 1467335 6 Milligram (mg) | Gamma-glutamyltransferase (GGT) After 12 Weeks of Treatment, Relative to Baseline in Percent | 99.51 Percentage relative to baseline | Standard Error 107.71 |
| BI 1467335 10 Milligram (mg) | Gamma-glutamyltransferase (GGT) After 12 Weeks of Treatment, Relative to Baseline in Percent | 83.70 Percentage relative to baseline | Standard Error 105.4 |
p-value: 0.129MCPMod exponential model fit.
Secondary
Percentage of Participants With Drug-related Adverse Events (AEs)
Percentage of participants with drug-related adverse events (AEs). Percentages are calculated using total number of patients per treatment as the denominator.
Time frame: Start of treatment till end of treatment + 28 days, up to 113 days.
Population: Treated Set (TS): All patients who signed the informed consent and were treated with at least one dose of the trial medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Drug-related Adverse Events (AEs) | 25.0 Percentage of participants |
| BI 1467335 1 Milligram (mg) | Percentage of Participants With Drug-related Adverse Events (AEs) | 31.3 Percentage of participants |
| BI 1467335 3 Milligram (mg) | Percentage of Participants With Drug-related Adverse Events (AEs) | 12.5 Percentage of participants |
| BI 1467335 6 Milligram (mg) | Percentage of Participants With Drug-related Adverse Events (AEs) | 11.8 Percentage of participants |
| BI 1467335 10 Milligram (mg) | Percentage of Participants With Drug-related Adverse Events (AEs) | 25.0 Percentage of participants |
Secondary
Total Cytokeratin 18 (CK-18 Total) After 12 Weeks of Treatment, Relative to Baseline in Percent
Total cytokeratin 18 (CK-18 total) after 12 weeks of treatment, relative to baseline in percent. Number analyzed lower than N in PPS if there is missing data for specific timepoints. The unit of measure is: percentage relative to baseline = \[post baseline (time t)/baseline\]\*100%. Statistical analyses description: A Mixed effects Model for Repeated Measurements (MMRM) over time including fixed effects for 'base', 'treatment', 'time', 'base\*time' interaction, and 'treatment\*time' interaction was performed. The MMRM estimates for the treatment effects at Week 12 and the corresponding covariance matrix were used to analyse the dose-response relationship using the Multiple contrast test (MCPMod). A test for non-flat dose-response relationship was first performed. If this relationship could be shown, the best fitting model out of a set of candidate models (Sigmoidal Emax, Logistic, Quadratic, Linear, Exponential, Linear logistic, Emax and Betamod) was to be selected and fitted.
Time frame: Day 1 (baseline), day 15, 29, 43, 57 and 85 (time t) 24 hours after the last dose of BI 1467335.
Population: Per Protocol Set (PPS): patients who signed informed consent, were treated with at least one dose of the trial medication, without any important protocol deviations leading to exclusion and who had non-missing baseline and at least one non-missing post-baseline and on-treatment measurement on any primary, secondary or further biomarker endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Total Cytokeratin 18 (CK-18 Total) After 12 Weeks of Treatment, Relative to Baseline in Percent | 92.44 Percentage relative to baseline | Standard Error 109.13 |
| BI 1467335 1 Milligram (mg) | Total Cytokeratin 18 (CK-18 Total) After 12 Weeks of Treatment, Relative to Baseline in Percent | 128.33 Percentage relative to baseline | Standard Error 114.64 |
| BI 1467335 3 Milligram (mg) | Total Cytokeratin 18 (CK-18 Total) After 12 Weeks of Treatment, Relative to Baseline in Percent | 99.56 Percentage relative to baseline | Standard Error 113.78 |
| BI 1467335 6 Milligram (mg) | Total Cytokeratin 18 (CK-18 Total) After 12 Weeks of Treatment, Relative to Baseline in Percent | 94.74 Percentage relative to baseline | Standard Error 113.1 |
| BI 1467335 10 Milligram (mg) | Total Cytokeratin 18 (CK-18 Total) After 12 Weeks of Treatment, Relative to Baseline in Percent | 81.47 Percentage relative to baseline | Standard Error 109.35 |
p-value: 0.0728MCPMod exponential model fit.